Diabetes mellitus is a disease of major global importance that has increased in frequency at almost epidemic rates. The worldwide prevalence in 2006 is 170 million people and is predicted to at least double over the next 10-15 years. Diabetes is characterized by a chronically raised blood glucose concentration (hyperglycemia), due to a relative or absolute lack of the pancreatic hormone, insulin. Within the healthy pancreas, beta cells, located in the islets of Langerhans, continuously produce and secrete insulin according to the blood glucose levels, maintaining near constant glucose levels in the body.
Much of the burden of the disease to the user and to health care resources can occur due to long-term tissue complications that affect both the small blood vessels (microangiopathy, causing eye, kidney and nerve damage) and the large blood vessels (causing accelerated atherosclerosis, with increased rates of coronary heart disease, peripheral vascular disease and stroke). The Diabetes Control and Complications Trial (DCCT) has demonstrated that development and progression of the chronic complications of diabetes are greatly related to the degree of altered glycemia as quantified by determinations of glycohemoglobin (HbAlc). (DCCT Trial, N. Engl. J. Med 1993; 329: 977-986, UKPDS Trial, Lancet 1998; 352: 837-853. BMJ 1998; 317, (7160): 703-13 and the EDIC Trial, N. Engl. J. Med. 2005; 353, (25): 2643-53). Thus, maintaining normolycemia by frequent glucose measurements and adjustment of insulin delivery accordingly can be quite important.
The glycemic index (GI) is a ranking system for carbohydrates based on their effect on blood glucose levels in the first two hours. Table 1 shows a few examples of foods and their GI.
TABLE 1Glycemic index ranges and classifications for selected foods.ClassificationGI RangeExamplesLow GI55 or lessMost fruit and vegetables (but not potato),oats, buckwheat, whole barley, All-branMedium GI56-69Sucrose, basmati riceHigh GI70 or moreCorn flakes, baked potato, jasmine rice,white bread, white rice, Mars bar
An after-meal or post-prandial glycemic peak (hyperglycemia) is defined as the net rise in a patient's blood glucose concentration that occurs from before eating to the highest point after eating. The ADA goal for diabetic treatment is a glucose concentration level that is less than 180 mg dl″1 at approximately 1-2 hrs after the start of meal. Increasing evidence suggests that postprandial hyperglycemia is a contributing factor to the development of atherosclerosis. The postprandial phase can be characterized by a rapid and large increase in blood glucose levels. The association of postprandial “hyperglycemic spikes” with the onset of cardiovascular complications has recently received much attention. Postprandial hyperglycemia can be a direct and independent risk factor for cardiovascular disease (CVD). The mechanisms through which acute hyperglycemia exerts its effects may be identified in the production of free radicals. Correcting the postprandial hyperglycemia may form part of the strategy for the prevention and management of CVDs in diabetes {Diabetes 2005; 54:1-7). Other, short term problems, such as for example tiredness, concentration difficulties, decreased desire to move, mood shifts, and enhanced hunger, can also be attributed to postprandial hyperglycemia. As such, prevention of post-prandial hyperglycemia can be quite important.
Currently, the strategies used by diabetic patients for prevention of post-prandial hyperglycemia are divided into lifestyle approaches and medicinal approaches. Lifestyle approaches are mainly dietary. For example, a patient's diet can be restricted to intake of food that convert slowly to glucose, such as high fiber food. Timing of insulin boluses can also help lower post-prandial hyperglycemic peaks. Medicinal approaches include agents such as exenatide (Byetta) and pramlintide acetate (Symlin).
Amylin is a second β-cell hormone that is co-localized and co-secreted with insulin in response to meals. Consequently, β-cell dysfunction in insulin-requiring subjects with type 1 or type 2 diabetes is characterized by a markedly impaired postprandial secretory response of both insulin and amylin. Amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation through several centrally mediated effects that can include a suppression of postprandial glucagon secretion and a vagus-mediated regulation of gastric emptying, thereby helping to control the influx of endogenous and exogenous glucose, respectively. Amylin has also been shown to reduce food intake and body weight, consistent with an additional satiety effect. Consistent with these findings, mealtime amylin replacement, as an adjunctive therapy to insulin delivery, can improve metabolic control in diabetic subjects.
FIG. 1 shows the co-secretion of amylin and insulin in response to meals in a healthy subject. Both hormones are co-localized in the β-cells of the pancreas. β-cell dysfunction in insulin-requiring subjects with type 1 or type 2 diabetes is characterized by a markedly impaired postprandial secretory response of both insulin and amylin.
Native human amylin is typically not ideal for clinical use because of the peptide's poor solubility and propensity to aggregate. Pramlintide is a soluble, non-aggregating synthetic peptide analog of human amylin that has a potency at least equal to that of native amylin. Pramlintide in insulin-requiring subjects with diabetes has been shown, as an adjunct to insulin therapy, to correct postprandial hyperglucagonemia, slow the delivery of nutrients from the stomach to the small intestine, and, concomitantly, improve postprandial glucose excursions (Diab. Tech. Therp. 2002; 4(1):51-61).
Pramlintide can be injected subcutaneously with a standard insulin syringe, rendering the dosage flexible. For weight loss, maximum doses are administered and for normalizing postprandial glucose levels, lower doses are indicated. The dosing recommended by the manufacturer for normalizing post-prandial glucose levels are the following: starting with 2.5 units and increasing to 5 units, then 7.5 units, and 10 units before each meal if no nausea is encountered for three consecutive days.
FIG. 2 shows mean (±SE) values for seven-point glucose profiles performed before (open circles) and after 6 months (solid circles) of pramlintide therapy in patients with type 2 diabetics on insulin therapy. The blood glucose concentrations were assessed within 0.5 h before and 1.5-2 h after breakfast, lunch, and dinner and at bedtime. It can be seen that both fasting and postprandial glucose concentrations were significantly reduced compared to baseline (P<0.05). (Diabetes Technology & Therapeutics 2007; 9 (2): 191-99.)
Insulin pumps can be used to deliver rapid acting insulin to a diabetic patient 24 hours a day through a catheter placed under the skin (subcutaneously). The total daily insulin dose can be divided into basal and bolus doses. Basal insulin can be delivered continuously, semi-continuously, or periodically over 24 hours, thereby maintaining the blood glucose concentration level (namely, blood glucose levels) within a normal, desirable range between meals and overnight. Diurnal basal rates can be pre-programmed or manually changed according to various daily activities. Insulin bolus doses can be delivered before or after meals to counteract carbohydrates loads or during episodes of high blood glucose concentration levels.